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2022 Sep 26

Cell Rep Med

Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients.


LaSalle TJ, Gonye ALK, Freeman SS, Kaplonek P, Gushterova I, Kays KR, Manakongtreecheep K, Tantivit J, Rojas-Lopez M, Russo BC, Sharma N, Thomas MF, Lavin-Parsons KM, Lilly BM, Mckaig BN, Charland NC, Khanna HK, Lodenstein CL, Margolin JD, Blaum EM, et al.
Cell Rep Med. 2022 Sep 26:100779.
PMID: 36208629.


Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19 patients and 86 controls and perform bulk RNA sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between six distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.